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With Top-line Deep-C Trial Data, Exact Sciences Gears Up for FDA and CMS Submissions for Cologuard

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Originally published April 23.

After releasing top-line results from the DeeP-C trial of its Cologuard test, Exact Sciences' priority is to quickly analyze the full data from the pivotal study and submit the relevant information to the US Food and Drug Administration for regulatory review and to the Centers for Medicare & Medicaid Services for a national coverage determination.

Last week, Exact Sciences reported preliminary data from the trial involving 10,000 patients at average risk of developing colorectal cancer. The study aimed to establish the sensitivity and specificity of Cologuard and to compare the DNA test's ability to detect colorectal cancer and pre-cancerous polyps against the standard of care, colonoscopy.

According to the data released so far, Cologuard was able to detect cancer with 92 percent sensitivity, detect pre-cancerous polyps that were 1 cm or larger with 42 percent sensitivity, and detect pre-cancerous polyps that were 2 cm or larger with 66 percent sensitivity. The test demonstrated specificity – the ability to detect patients who following colonoscopy and histopathological analysis were found to not have cancer or pre-cancerous polyps – of 87 percent.

"While the analysis of the full clinical trial data has just begun, this preliminary top-line data gives us great confidence for a strong submission to the FDA," Exact Sciences CEO Kevin Conroy told analysts during a call to announce the DeeP-C results.

DeeP-C also included secondary endpoints, such as looking at the sensitivity and specificity of Cologuard to detect advanced adenomas and gauging whether the genetic test was non-inferior to fecal immunochemical testing, a non-invasive method of detecting colorectal cancer, for cancer sensitivity and superior to FIT for advanced adenoma sensitivity. Conroy highlighted during the call that in DeeP-C Cologuard was non-inferior for cancer sensitivity and superior for pre-cancer sensitivity compared to FIT, but did not provide specific numbers.

According to Exact Sciences, DeeP-C is one of the largest colorectal cancer screening studies conducted in the US. The trial enrolled patients at 90 sites and included 64 patients with colorectal cancer and 752 patients with pre-cancerous polyps. Investigators collected a stool sample from study participants for analysis by Cologuard and FIT. Study participants had a colonoscopy within 90 days of being enrolled in DeeP-C, so that their Cologuard test results could be compared to their colonoscopy results and to the histopathlogical analysis of their lesions.

Although Exact Sciences said that Cologuard met the trial endpoints for cancer and pre-cancer sensitivity, the test's performance fell somewhat short of previously announced targets. Mizuho Securities analyst Peter Lawson said in a research note that the 87 percent specificity seen for Cologuard in DeeP-C failed to meet the previously stated goal of 90 percent. Additionally, the 42 percent test sensitivity for detecting precancerous polyps 1 cm or larger didn't meet an internal target of 50 percent.

Conroy highlighted, however, that the 66 percent sensitivity for Cologuard in detecting pre-cancerous polyps of 2 cm or larger "is very powerful." The risk of colorectal cancer increases with the size of the pre-cancerous polyps. Conroy cited data to note that fewer than 40 percent of polyps continue to grow past 1 cm, and those that do grow, do so very slowly, doubling in size within five to six years. "The slow growth of these polyps gives us ample time to detect them over several screening intervals, which creates a cumulative sensitivity of potentially 90 percent," Conroy noted.

The DeeP-C trial did not test patients' stool over treatment intervals. However, in the real world, the screening DNA test will likely be performed on patients once every few years. For example, in its 2000 guidelines, the American College of Gastroenterology recommended that doctors screen patients for colorectal cancer using fecal DNA tests every three years as an alternative cancer detection method.

Likening Cologuard to cervical cancer screening with pap smears, Exact Sciences believes that the sensitivity of its colorectal cancer test will increase with repeated testing over the continuum of a patient's care. "The fight against cervical cancer has been so successful because it has focused on two things: pre-cancer detection and repeat testing over time," Conroy told analysts. "Repeat testing enables the detection of more pre-cancers, increasing programmatic sensitivity. This is precisely how we believe Cologuard could be used and the potential it has to affect public health."

After Exact Sciences completes its analysis of all the Deep-C data, the company plans to finish its rolling pre-market approval submission to the FDA. "We believe that our modular submission will provide some efficiencies in the timing of the agency's review," Conroy said. The company also expects that as part of its regulatory review, the FDA will engage an advisory committee review of the Deep-C data.

"In parallel, we will complete and submit our Medicare national coverage application to the [Centers for Medicare & Medicaid Services]," Conroy said. Additionally, the company is hoping to publish the full Deep-C data in a peer-reviewed publication later this year and present the clinical trial findings in more detail at an upcoming conference.

Exact Sciences volunteered to take Cologuard through FDA and CMS's Parallel Review pilot project over a year ago. CMS and FDA's Center for Devices and Radiological Health launched the parallel review pilot in October 2011 in an effort to create a framework for conducting concurrent reviews of innovative devices that require premarket approval from the FDA and qualify for a national coverage determination – a six- to nine-month process by which CMS determines if it will pay for a product or service that it deems "reasonable and necessary" for the Medicare population. Through this pilot, the agencies are hoping to reduce the time it takes a company to commercially launch a medical device and garner reimbursement coverage.

Conroy has previously stated that the parallel review program was "critical" to the company's success. According to him, participation in the pilot shaved off two years from the time it would have otherwise taken the company to garner FDA approval and Medicare coverage, and it allowed the firm to save money by conducing one well-powered study to meet the requirements of two agencies (PGx Reporter 4/3/2013).

Conroy believes that Exact Sciences, having taken Cologuard through parallel review, will be able to obtain a quick national coverage decision from CMS, as well as a temporary Medicare claims processing code and payment level. He estimated that private payors typically pay around $2,400 for a colonoscopy procedure. "We expect [Cologuard] to be priced at a very reasonable price point relative to colonoscopy."

Exact Sciences is on a "tight timeline" to complete its Cologuard submissions to the two agencies, Conroy noted adding that the firm is working to make its regulatory and reimbursement submissions to the relevant agencies by May or June. He assured analysts that the company will provide more definitive guidance on the submission timeline during its next earnings call.

Although top-line DeeP-C results didn’t meet certain internal goals, Exact Sciences is maintaining its original commercialization strategy to target Cologuard sales pitches to large groups of physicians that make top-down decisions about screening. These types of practices employ nearly 50 percent of US doctors. Exact Sciences will also aim to drive adoption of Cologuard among the 2,000 doctors who prescribe around 1 million FIT and fecal occult blood tests. "We will focus on those two groups at launch, and then expand as time goes forward," Conroy said.

Referring to the results that were slightly below expectations, Conroy noted that the company doesn't believe this will be "an impediment in any way to the ultimate successful adoption of this test by physicians and patients."

Exact Sciences is hoping that its stool-based, non-invasive test will improve screening rates among those at risk for colorectal cancer. "We didn't expect the specificity to be at 87 percent, but the thing to note … is that the underlying problem here … is that only 50 percent of patients who should be screened for colon cancer are screened for colon cancer," Conroy said. "By increasing the percentage of people who are willing to be screened with a patient-friendly test, you can have a significant impact on the human toll caused by this disease and also the financial burden, the $14 billion a year we spend treating the disease."

Cologuard analyzes genetic alterations associated with colorectal cancer and pre-cancerous conditions in patients' stool samples. Currently, doctors screen patients for colorectal cancer primarily via colonoscopy, an invasive procedure that allows physicians to look for signs of cancer by inserting a tube with a camera through the rectum and into the colon.

There are non-invasive screening methods, such as FIT or fecal occult blood testing, but previously published data suggest that these methods have lower sensitivity to gauge colorectal cancer (66 percent and 12.9 percent, respectively). "Although these tests are widely utilized, they are not very effective in detecting cancers," Conroy said. "And their pre-cancer detection rate is abysmally low."

If fecal immunochemical and occult blood tests identify blood in the stool sample, then the patient will likely require additional diagnosis with colonoscopy, which has been shown to have 95 percent sensitivity to detect cancer. Comparatively, Cologuard, with 92 percent sensitivity, has "virtually the same" sensitivity as colonoscopy, Conroy told PGx Reporter. Additionally, Cologuard "detects pre-cancers, particularly those most likely to turn into cancers, at the same rate as the pap smear detects cervical pre-cancers."

Once Cologuard is launched, Exact Sciences is planning to offer a service that makes "it incredibly easy for a doctor to order this test for their patient," Conroy said on the call. "If the doctor orders the test, our job … is to get that patient screened and follow up with the patient … because your total effectiveness in a screening program depends on the [patient's] overall compliance rate."

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